Multiple different biochemical defects have been identified in patients with genetic forms of extreme insulin resistance. These defects have included: (1) a decreased number of insulin receptors, (2) qualitatively abnormal insulin receptors which are impaired in their ability to couple insulin binding to insulin action; and (3) post-receptor defects in insulin action. Cultured Epstein-Barr virus-transformed lymphocytes from insulin resistant patients have been used to study biosynthesis and turnover of insulin receptors. In those patients with a decreased number of insulin receptors there is a marked (about 90%) decrease in receptor biosynthesis with only a slight increase in the rate of receptor degradation. In other patients, whose circulating monocytes possess a normal number of insulin receptors despite hyperinsulinemia, it was not clear why the hyperinsulinemia did not lead to down-regulation of receptors. However in cultured EBV-transformed lymphocytes from these patients down regulation of their insulin receptor could be demonstrated.